The SUKI Foundation presents the "5th Annual Raise the Roof for Rett" on Friday, October 28, 2016 at Haven.  The Foundation is a not-for-profit organization created in honor of Sarah Katherine following her diagnosis of Rett Syndrome.  Dr. Alan Percy, Civitan interim director, was featured in the new Rett Syndrome video which spotlights the Suki Foundation and the upcoming fund raiser. http://sukifoundation.org/index.html
UAB researchers use expanded computing power to accelerate big-data science by Jeff Hansen

Computing challenges are found across the UAB campus, from physics and neurology to genetics and the microbiome. Alabama’s most advanced supercomputer is now at UAB, making it possible to solve these challenges. 

Kristina VisscherKristina Visscher is using fMRI images from several hundred brains to learn how the brain adapts after long-term changes in vision.What do the human brain, the 3 billion base-pair human genome and a tiny cube of 216 atoms have in common?

All of them, from the tiny cube to the 3-pound human brain, create incredibly complex computing challenges for University of Alabama at Birmingham researchers, and aggressive investments in UAB’s IT infrastructure have opened new possibilities in innovation, discovery and patient care.

For example, Kristina Visscher, Ph.D., assistant professor of neurobiology, UAB School of Medicine, uses fMRI images from several hundred human brains to learn how the brain adapts after long-term changes in visual input, such as macular degeneration. Frank Skidmore, M.D., an assistant professor of neurology in the School of Medicine, studies hundreds of brain MRI images to see if they can predict Parkinson’s disease.

David Crossman, Ph.D., bioinformatics director in UAB’s Heflin Center for Genomic Science, deciphers the sequences of human genomes for patients seeking a diagnosis in UAB’s Undiagnosed Diseases Program, and he processes DNA sequencing for UAB researchers who need last-minute data for their research grant applications.

Ryoichi Kawai, Ph.D., an associate professor of physics in the UAB College of Arts and Sciences, is laying the groundwork for a better infrared laser by calculating the electronic structure for a cube made up of just 216 atoms of zinc sulfide doped with chromium or iron.

Each researcher faces a mountain range of computational challenges. Those mountains are now easier to scale with UAB’s new supercomputer — the most advanced in Alabama for speed and memory.

The tiny cube

The 216-atom electronic structure problem “is the largest calculation on campus, by far,” Kawai said. “If you give me 2,000 cores, I can use them. If you give me 10,000 cores, I can use them all without losing efficiency.” (UAB's new supercomputer has 2,304 cores.)

supercomputer infographic thumb Learn more about UAB’s new supercomputer in this story

Using 1,000 cores, it would take two to three months of continuous computing to solve the structure, Kawai says. Both the increased number of cores and faster processing nodes in the new computer cluster will speed up that task so much that Kawai’s graduate student Kyle Bentley can investigate more different cases.

Brains

In their research, both Skidmore and Visscher have to compare brains with other brains. Because each brain differs somewhat in size, shape and surface folds, every brain has to be mapped onto a template to allow comparisons.

Physicist Kawai describes his computations as the most intensive on campus.“We want to capture information in an image, such as information on an individual’s brain condition,” Skidmore said. “The information we are trying capture, however, can often be difficult to see in the sea of data we collect. One brain may contain millions of bits of data in the form of ‘voxels,’ which are a bit like the pixels on your TV but in three dimensions.”

“When we map to a template,” Skidmore said, “we quadruple the data. When we ask, ‘How does this compare to a healthy brain?’ we double the data again. Then if we look across one brain or across multiple kinds of brain images, the amount of data truly explodes.”

news jeff supercomputer kawaiPhysicist Ryoichi Kawai's complex calculations of the electronic structure of a cube of atoms are laying the groundwork for better lasers.“This is made even more complex by the fact that a given image can include more than three dimensions of information,” he said. “One type of image we use generates 5-dimensional brain maps. Since we can’t see in five dimensions, we ask the computer to work in these higher-dimensional spaces to help us pull the information out of the data.”

To look at the adult brain’s plasticity — the ability to change function and structure through new synaptic connections — Visscher studies visual processing.

“Because we look at spatial and temporal data, the number of pieces of information is huge — gigabytes per subject,” she said. “We need to do correlations on all the data points at the same time. To get faster, we optimize the data analysis with a lot of feedback. Then we run what we learned from one brain on a hundred brains.”

UAB customers

Crossman deciphers the sequences of human genomes for patients seeking a diagnosis, and he processes DNA sequencing for UAB researchers. Providing excellent customer service to his clients is vital, Crossman says, and it takes computer power to crunch genome sequencing data for those researchers, physicians and patients.

Managing traffic on the new UAB computer cluster

Size:

  • The new cluster has 2,304 cores. It also has eight accelerators, composed of four Nvidia K80 GPU cards and four Intel Xeon Phi 7210 accelerators.
Queues:

  • While one could use all of these processors as a single job, a queuing system exists to make sure one user does not take over the entire cluster. The different number of cores used in a queue are allocated based on the users’ requests.
Scheduling

  • User jobs differ in terms of how many cores they need and how long each job takes to run. To balance these conflicting demands, a scheduler considers the availability of the cores, how many jobs a user is already running and how long the new job will run.
The new supercomputer “will drastically improve our computing capacity from what we have had,” Crossman said. “With the old cluster, my job might sit in a queue for a couple of weeks. With undiagnosed diseases, that is not acceptable because that’s a patient.”“And I cannot tell a researcher, ‘I’m sorry, we won’t meet that grant deadline,’” Crossman said. “You know, science can’t stop.”

The data floodgates of genomics burst open about a dozen years ago with the arrival of next-generation, high-throughput sequencing, says Elliot Lefkowitz, Ph.D., director of Informatics for the UAB Center for Clinical and Translational Science. Lefkowitz has been serving the bioinformatics needs of the UAB Center for AIDS Research for 25 years, and now also handles bioinformatics for the UAB Microbiome Facility. His team has grown to five bioinformaticians and several programmers.

“We deal with billions of sequences when we do a run through the DNA sequencing machine,” Lefkowitz said. “We need to compare every one of the billion ‘reads’ (the 50- to 300-base sequence of a short piece of DNA) to every other one. With high-performance computing and thousands of nodes, each one does part of the job.”

“In not too many years,” Lefkowitz speculated, “we will be sequencing every patient coming into University Hospital.”

Changes like that mean ever-increasing computer demands.

“Biomedical research,” Crossman said, “now is big data.”
The UAB Research Civitan Club will be hosting a large charity art auction in October and would like for you to be a part of it!  “The Art of Giving” will be held at the Civitan International Research Center at UAB on Thursday October 20th starting at 6:00 p.m.

All proceeds from the event will be donated to Mitchell’s Place, a local charity to benefit autistic children and their families. The mission of Mitchell’s Place is to provide comprehensive, research-based, educational, social, and therapeutic services for children, adolescents, and families affected by Autism Spectrum Disorder. The  donation will help provide programming and resources to benefit the families they serve.  The event is expected to draw over 300 supporters and the artwork is the star of the show! We are requesting the donation of a piece of artwork that can be placed in a silent auction. Any piece of work, no matter how large or small, is an opportunity to spread some good in the world. Thank you for your consideration of this request, and know what a difference your donation makes!

If you would like to donate a piece of art or make a monetary donation, please contact Katie King at kking210@bellsouth.net or Tiffany Alexander at tiffanyalexander@uab.edu.
Discovery may lead to a treatment to slow Parkinson’s disease



Researchers have found that an interaction between a mutant gene and alpha synuclein in neurons leads to hallmark pathologies seen in Parkinson’s disease, findings that may lead to new mechanisms and targets for neuroprotection.

laura volpicelliLaura A. Volpicelli-DaleyUsing a robust model for Parkinson’s disease, University of Alabama at Birmingham researchers and colleagues have discovered an interaction in neurons that contributes to Parkinson’s disease, and they have shown that drugs now under development may block the process.

The research team has shown that the most common genetic cause of Parkinson’s disease — a mutant LRRK2 kinase enzyme — contributes to the formation of inclusions in neurons, resembling one of the hallmark pathologies seen in Parkinson’s disease. These inclusions are made up of aggregated alpha synuclein protein, which — the research also shows — can be prevented from forming by using two LRRK2 kinase inhibitor drugs now being developed for clinical use.

The interaction between mutant LRRK2 kinase and alpha-synuclein “may uncover new mechanisms and targets for neuroprotection,” the researchers write in a recent Journal of Neuroscience paper. “These results demonstrate that alpha-synuclein inclusion formation in neurons can be blocked and that novel therapeutic compounds targeting this process by inhibiting LRRK2 kinase activity may slow progression of Parkinson’s disease-associated pathology.”

The potential clinical applications for novel neuroprotection strategies in LRRK2-linked Parkinson’s need to be tested in other preclinical models of Parkinson’s disease, say the researchers, led by corresponding author Laura A. Volpicelli-Daley, Ph.D., and senior author Andrew B. West, Ph.D., Center for Neurodegeneration and Experimental Therapeutics, UAB Department of Neurology.

“These data give us hope for the clinical potential of LRRK2 kinase inhibitors as effective therapies for Parkinson’s disease,” Volpicelli-Daley said. “The LRRK2 kinase inhibitors may inhibit the spread of pathologic alpha-synuclein, not only in patients with LRRK2 mutations, but in all Parkinson’s disease patients. Future studies to validate the safety and efficacy of the LRRK2 inhibitors will be necessary before testing the inhibitors in human clinical trials.”

Besides Parkinson’s disease, alpha-synuclein also plays a central role in development of dementia with Lewy bodies and multiple system atrophy, and it is associated with Alzheimer’s disease and other neurodegenerative disorders.

parkinsons andy westPrimary hippocampal neurons from mice expressing G2019S-LRRK2. The neurons were treated with alpha-synuclein fibrils, and 18 days later immunofluorescence was performed. The magenta shows phospho-alpha-synuclein inclusions in the cell bodies and throughout the axons, which are visualized as green.Research details

The Parkinson’s disease model developed by Volpicelli-Daley applies very low concentrations of pre-formed fibrils of alpha-synuclein to in vitro or in vivo neurons. This causes formation of modified alpha-synuclein inclusions that share morphology with those found in the Parkinson’s disease brain after death.

They used this model to test the effects of neuron expression of the mutant LRRK2 (“lark two”) kinase, G2019S-LRRK2, on the formation of the inclusion pathology.

They found that:

  • G2019S-LRRK2 enhanced alpha-synuclein inclusions in primary hippocampal neurons from the hippocampus region of the brain, 18 days after fibril exposure, as compared with neurons that over-expressed normal LRRK2.
  • The effects of G2019S-LRRK2 expression in the fibril-exposed neurons were lessened by very low concentrations of potent and selective preclinical drugs that inhibit LRRK2 kinase. This suggested that the kinase activity of G2019S-LRRK2, which adds a phosphate onto target proteins, underlies the faster formation of pathologic alpha-synuclein inclusions.
  • G2019S-LRRK2 expression enhanced alpha-synuclein inclusion formation in dopamine neurons from the region of the brain called the substantia nigra pars compacta. The substantia nigra pars compacta is the area of the brain that dies in Parkinson’s disease, so this experiment further supports a link between the G2019S-LRRK2 mutation and Parkinson’s pathogenesis.
As a control, they used anti-sense oligonucleotides to knock down the expression endogenous alpha-synuclein in neurons that expressed G2019S-LRRK2, and this prevented formation of inclusions.

andy westAndrew B. WestIn fluorescence-recovery-after-photobleaching experiments, they found there was a larger pool of mobile alpha-synuclein, as opposed to membrane-bound alpha-synuclein, in neurons that expressed G2019S-LRRK2. Recent work by others has shown that mobile alpha-synuclein is prone to misfolding and aggregation, so the researchers hypothesize that the G2019S-LRRK2 mutation may contribute to Parkinson’s susceptibility by boosting the amounts of mobile alpha-synuclein in neurons.

Besides Volpicelli-Daley and West, co-authors of the paper “G2019S-LRRK2 expression augments alpha-synuclein sequestration into inclusions in neurons” are Hisham Abdelmotilib, Zhiyong Liu, Lindsay Stoyka, João Paulo Lima Daher and Kyle Fraser, all of the Center for Neurodegeneration and Experimental Therapeutics, UAB Department of Neurology; Austen J. Milnerwood, Centre for Applied Neurogenetics, University of British Columbia; Vivek K. Unni, Jungers Center for Neurosciences Research and Parkinson Center of Oregon, Oregon Health & Science University; Warren D. Hirst, Pfizer Neuroscience and Pain Research Unit, Cambridge, Massachusetts; Zhenyu Yue, Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai; Hien T. Zhao, Ionis Pharmaceuticals, Carlsbad, California; and Richard E. Kennedy, Comprehensive Center for Healthy Aging and Division of Gerontology, Geriatrics, and Palliative Care, UAB Department of Medicine.

Grants to fund this work came from the American Parkinson’s Disease Association, the Michael J. Fox Foundation LEAPS Award and the National Institutes of Health NS064934.

Volpicelli-Daley is an assistant professor in the Department of Neurology.

West is co-director of the Center for Neurodegeneration and Experimental Therapeutics, and the John A. and Ruth R. Jurenko Professor of Neurology at UAB.